Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

RETROVIR (NDA-019655)

(ZIDOVUDINE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/10/2018 (SUPPL-58)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(additions underline)

…

Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see Data).

…

Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Dosage and Administration in Neonates

Due to the small volume of RETROVIR administered to neonates, advise caregivers to use an appropriate-sized syringe with 0.1-mL graduation to ensure accurate dosing of the syrup formulation.

…

11/28/2017 (SUPPL-57)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Allergic Reaction to Latex

(Additions and/or revisions are underlined; subsection title has been revised)

The vial stoppers for RETROVIR injection contain dry natural rubber (a latex derivative) which may cause allergic reactions in latex-sensitive individuals.

5.4 Lactic Acidosis and Severe Hepatomegaly with Steatosis

(Additions and/or revisions are underlined)

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including zidovudine. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with RETROVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

5.7 Lipoatrophy

(Newly added subsection)

Treatment with zidovudine has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take

months to years after switching to a non-zidovudine-containing regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine and other zidovudine- containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Allergic Reaction to Latex

Advise latex-sensitive patients that vial stoppers for RETROVIR injection contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex.

Lipoatrophy

Advise patients that loss of subcutaneous fat may occur in patients receiving RETROVIR and that they will be regularly assessed during therapy.

04/10/2017 (SUPPL-56)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Data

Human Data: …The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens.

02/24/2017 (SUPPL-55)

Approved Drug Label (PDF)

Boxed Warning

Additions underlined:

WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS

5 Warnings and Precautions

5.5 Use with Interferon- and Rebavirin-Based Regimans in HIV-1/HCV Co-infected Patients

RETROVIR replaces zidovudine throughout subsection.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion, as below:

Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RETROVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Available data from the APR show no difference in the overall risk of birth defects for zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population [see Data]. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.

In an animal reproduction study, administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose.

Data

Human Data: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine (2.9%) compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens.

A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV-1-transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo- treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received RETROVIR and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.

Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.

Animal Data: A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on gestation Day 6 through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose, which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.

8.2 Lactation

PLLR conversion, as below:

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Zidovudine is present in human milk. There is no information on the effects of zidovudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in a breastfed infant instruct mothers not to breastfeed if they are receiving RETROVIR.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Lactic Acidosis/Hepatomegaly with Steatosis

Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking RETROVIR if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when RETROVIR is started.

Drug Interactions

Advise patients that other medications may interact with RETROVIR and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of RETROVIR.

Pregnancy

Inform pregnant women considering the use of RETROVIR during pregnancy for prevention of HIV-1 transmission to their infants that transmission may still occur in some cases despite therapy.

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RETROVIR during pregnancy.

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk.

Missed Dose

Instruct patients that if they miss a dose of RETROVIR, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose.